Project 2: Serologic and molecular determinants of COVID-19 severity and immune protection

项目 2：COVID-19 严重程度和免疫保护的血清学和分子决定因素

• 批准号: 10688394
• 负责人: Linda J. Saif
• 金额: $ 59.98万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10688394
• 关键词: 2019-nCoV; ACE2; Age; Animals; Antibodies; Antibody Response; Antibody-Dependent Enhancement; Binding; Biological Assay; Blood; COVID-19; COVID-19 monitoring; COVID-19 pandemic; COVID-19 severity; Child; Clinical; Common Cold; Data; Data Set; Development; Diagnostic; Disease; Disease Outcome; Elderly; Enzyme-Linked Immunosorbent Assay; Epitopes; Exposure to; Family; Frequencies; Future; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Goals; Household; Human; Immune; Immune response; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin M; Immunologic Factors; Immunologist; Immunoprecipitation; Individual; Infection; Infection prevention; Integration Host Factors; Kinetics; Knowledge; Lead; Link; Luciferases; Measures; Mediating; Middle East Respiratory Syndrome Coronavirus; Molecular; Mucosal Immune Responses; Mucous Membrane; Mutation; Open Reading Frames; Outcome; Patients; Pattern; Peptides; Population; Prevalence; Prevention strategy; Proteins; Protocols documentation; Public Health; Reverse Transcriptase Polymerase Chain Reaction; Risk; SARS coronavirus; SARS-CoV-2 antibody; SARS-CoV-2 infection; SARS-CoV-2 pathogenesis; SARS-CoV-2 transmission; Sampling; Serology; Serology test; Serum; Severities; Severity of illness; Source; Specificity; Symptoms; Testing; Vaccinated; Vaccinee; Vaccines; Viral; Viral Proteins; Virus; betacoronavirus; career; co-infection; cohort; comorbidity; coronavirus disease; first responder; gene induction; high risk; human coronavirus; improved outcome; infection risk; innovation; insight; member; mucosal site; neutralizing antibody; novel; response; screening; seropositive; severe COVID-19; transcriptome; transcriptome sequencing; tumor-immune system interactions; vaccine-induced immunity

Project 2 Summary PROJECT 2. Serologic and molecular determinants of COVID-19 severity and immune protection. Unresolved scientific questions remain about how the type, kinetics and duration of SARS-CoV-2 serologic responses correlate with patient age, disease severity, protective immunity, and risk of spread to close contacts. Our overall goal is to utilize the well-annotated STOP-COVID data sets and longitudinal samples collected from the first-responder cohort (at high-risk for re-exposure) and family contacts (Project 1, Core B) to advance understanding of the specific host and viral factors that underlie long-lasting and protective serologic responses. Our three highly interactive aims include: to identify differences in virus neutralizing (VN) antibody isotypes and their target viral proteins/peptides/epitopes; to assess cross-protective immunity versus disease exacerbation by antibodies to common cold CoVs; and to probe, by virus-host transcriptome analysis, how SARS-CoV titer or sequence and initial immune response at mucosal sites or blood interrelate with disease outcomes and the above serologic responses. Aim 1: Define immunoglobulin isotypes, titer, target proteins and viral neutralization activity of SARS-CoV-2 specific Abs and their correlations with disease severity and protection: We will utilize VN assays (VNA) and a luciferase immunoprecipitation assay to identify VN antibody isotype specificities and their immunodominant and unique target viral proteins/peptides/epitopes relevant to disease severity and protection. Expected outcomes include data that delineate the temporal antibody isotypes and viral targets to refine protocols for serologic testing that align with protective immunity. Aim 2: Determine the impact of common cold CoVs (CCCoV) and SARS-CoV-2 specific antibodies on COVID-19 protection and disease severity in a high-exposure risk cohort of first responders and their household contacts. Diagnostic serum samples will be used in innovative ELISA platforms directed against unique and conserved CCCoV peptides, and Spike pseudotyped CCCoV to assess CCCoV antibody responses. Expected outcomes include original data on whether pre-existing CCCoV antibodies relate to COVID-19 clinical symptoms, severity or strain specificity of SARS-CoV-2 infection (Aim 3), or re-infection risk. Aim 3. Correlate patterns of mucosal and serologic immune responses with virus and host genetics. We will utilize a novel targeted host-SARS-CoV-2 RNA sequencing assay (CoV-DXVX) to assess whether virus titer or functional alterations in SARS-CoV-2 S1, S2, N proteins or other ORFs impact disease presentation, progression and outcome. Host response measured by the profile and strength of mucosal or blood immune gene induction will be correlated with the duration, type and protective ability of these serologic responses and with the ones above. Once vaccines are deployed to our first-responder cohort, all 3 aims will pivot to analyze how the above serologic response profiles and host immune gene induction differ in vaccinated SARS-CoV-2 seronegative and seropositive individuals compared with the naturally-infected individuals.

项目2摘要 项目2。1o-19的血清学和分子决定因素，严重性和免疫保护。 关于SARS-COV-2血清学的类型，动力学和持续时间如何，未解决的科学问题仍然存在 反应与患者年龄，疾病严重程度，保护性免疫和差异的风险相关 联系人。我们的总体目标是利用良好的停止数据集和纵向样本 从第一响应者队列（以重新曝光的高风险）和家庭联系（项目1，核心B）收集到 对持久和保护性血清学的基础的特定宿主和病毒因素的预先理解 回答。我们的三个高度互动的目的包括：确定病毒中和（VN）抗体的差异 同种型及其靶标病毒蛋白/肽/表位；评估跨保护免疫与疾病 对普通冷COV的抗体加剧；并通过病毒宿主转录组分析来探测 SARS-COV滴度或序列和粘膜部位的初始免疫反应或血液与疾病相互关联 结果和上述血清学反应。目标1：定义免疫球蛋白同种型，滴度，靶蛋白和 SARS-COV-2特异性ABS的病毒中和活​​性及其与疾病严重程度的相关性 保护：我们将利用VN分析（VNA）和荧光素酶免疫沉淀测定法来鉴定VN抗体 同种型特异性及其免疫主导和独特的靶标病毒蛋白/肽/表位与 疾病的严重程度和保护。预期结果包括描绘时间抗体同型的数据 和病毒靶标，以完善与保护性免疫相一致的血清学测试方案。目标2：确定 普通冷COV（CCCOV）和SARS-COV-2特异性抗体对COVID-19保护和 高曝光风险急救人员及其家庭接触的疾病严重程度。诊断 血清样品将用于针对独特和保守的CCCOV的创新ELISA平台 肽和尖峰假型CCCOV评估CCCOV抗体反应。预期结果包括 原始数据有关现有的CCCOV抗体是否与Covid-19的临床症状，严重程度或 SARS-COV-2感染的应变特异性（AIM 3）或重新感染风险。目标3。粘膜和 病毒和宿主遗传学的血清学免疫反应。我们将利用一种新颖的目标宿主-SARS-COV-2 RNA测序测定（COV-DXVX）评估SARS-COV-2 S1中的病毒滴度或功能改变， S2，N蛋白或其他ORF会影响疾病的表现，进展和结果。主机响应 通过粘膜或血液免疫诱导的特征和强度来衡量将与 这些血清学反应以及上面的持续时间，类型和保护能力。一旦疫苗是疫苗 部署到我们的第一响应者队列，所有3个目标都将枢转，以分析上述血清学反应如何 概况和宿主免疫基因诱导在接种的SARS-COV-2血清阳性和血清阳性的疫苗接种量不同 与自然感染的个体相比。